10-25% of adult asthma is occupation-induced, a subtype caused by exposure to environmental irritants in the workplace. Recently, a genome-wide association study (GWAS) identified single nucleotide polymorphisms (SNPs) in ?-T-catenin (?-T-cat) that correlated with the incidence and severity of toluene diisocyanate (TDI) occupational asthma. ?-T-cat is an essential mediator of cardiac cell-cell adhesion through linking the ?-catenin/cadherin complex to the cytoskeleton, so a mechanism by which ?-T-cat could contribute to TDI-asthma has been unclear. We find, however, that ?-T-cat is indeed expressed in lung within the cardiomyocyte sheath of pulmonary veins (PV). How PV dysfunction might underlie asthma is not known, but ?-T-cat knockout (KO) mice manifest enlarged hearts with disrupted junctions and reduced contractility, and we find that the cardiomyocyte sheath of PV may be similarly thickened, suggesting a lung phenotype/genotype correlate. We also find that using a TDI-based murine model of asthma, ?-T-cat KO mice show increased airway hyperresponsiveness (AHR) to methacholine (mCh) when compared to WT mice, confirming that dysfunction of ?-T-cat may increase the sensitivity for the development of TDI-asthma. Based on these preliminary data, we suspect ?-T-cat dysfunction may contribute to asthma through a cardiac cell defect that leads to increased airway edema. ?-T-cat loss causes heart enlargement, perhaps due to its effect on limiting tissue proliferation through the Hippo-Warts (HW) pathway, an established regulator of cardiac growth that can be inhibited by the highly related ?-E-cat. In addition, cardiomyocytes of ?-T-cat KO mice manifest a reduction in hybrid junctions, composed of cadherin, desmosome, and gap junction components, which are critical for coordinated contractility. Since ?-T-cat can bind plakophilin-2 (PKP2), a component o desmosomes, we predict that a ?-Tcat/PKP2 interaction is critical to both the assembly of hybrid junctions, gap junction communication and proliferation inhibition. Together, the proposed aims will allow us to test the hypothesis that ?-T-cat dysfunction in cardiomyocytes disrupts gap junction communication and increases proliferation, which ultimately drive edematous changes that contribute to asthma. Together, these findings suggest that cardiac cell junction dysfunction may underlie occupational asthma. This is a novel mechanism and contributor to the pathogenesis of asthma, which has long been considered primarily a disease mediated by inflammation. By elucidating the influence of cardiac function on the development of asthma, we may be able to develop novel drugs targeting improving vascular and cardiac function to prevent or treat occupational asthma in susceptible individuals.